In the beginning of 20th century, the Nobel Prize winner German scientist Paul Ehrlich proposed the idea of “magic bullet” for future drug development, i.e., an ideal drug that would selectively destroy diseased cells without affecting healthy cells. In the past several decades, scientists have been exploring to develop such ideal drugs.
In the 1970s, targeted drug delivery system were developed and widely used for the treatment of cancer. Meanwhile, with the advancement of research, new targeted drug delivery carriers have, emerged, the routes of administration have, been broadened, and targeted drug delivery system have been expanded to treat many diseases other than cancer.
Developing targeted drugs for respiratory diseases is one of the hotspots, and it is primarily focused on the following areas:
1. Targeted treatment of airway diseases by inhalation.
Starting in the early 1950s, inhaled corticosteroids have been used for the treatment of asthma and COPD. Since then, with the improvement in inhaled drugs and devices, inhaled corticosteroids have become the main therapeutic agents for the treatment of asthma and COPD. However, inhaled drugs are mainly suitable for topical treatment of airway diseases, and are not effective against parenchyma and interstitial lung diseases due to low bioavailability.
Passive lung-targeting drugs through drug carriers.
2. Currently, a variety of drug carriers such as liposomes, microparticles, microspheres are used in the research of lung-targeted drug delivery. However, these passive targeting drug carriers have poor tissue selectivity, and cannot avoid significant residue in the liver, spleen and other organs. Therefore, they don't achieve optimal targeting effect.
The ligand-receptor or antigen-antibody binding is a special recognition mechanism of the human body, and it has been reported that the mechanism could achieve active drug targeting to enhance drug efficacy and reduce the side effects. For example, a composite drug made of paclitaxel liposomes and a monoclonal antibodies against the epidermal growth factor has anti-tumor effect 25 times greater then that of the drug without the monoclonal antibody. Thus, to achieve ideal active lung targeting effect, it is critical to find a receptor in the lung tissue with high specificity and prepare a targeting ligand with high affinity. Studies have shown that pulmonary alveolar type II epithelial cells which account for 16% of the total cells in lung parenchyma have proliferation and secretion functions. Type II cells can synthesize and secrete pulmonary surfactant. The main components of the pulmonary surfactant are lipids (90%) and proteins (10%), and the proteins are specific pulmonary surfactant proteins (SPs). SPs have been named as SP-A, SP-B, SP-C, SP-D, based on the order of discovery, and SP-A was first discovered and has strong expression in pulmonary alveolar type II epithelial cells with abundant signals, and is rarely expressed in other tissues. Thus, SP-A is highly lung-specific, and is an ideal receptor in the lung tissue with specificity.
In addition to high affinity, an ideal targeting ligand should have a low molecular weight, high tissue penetration, and weak immunogenicity. Antigen-antibody binding is the strongest recognition mechanism, and therefore an antibody is the preferred ligand. However, although of high affinity, full antibodies are not ideal ligands due to their large molecular weight (with a relative molecular weight of 150,000), weak tissue penetration and strong immunogenicity. With the development of antibody and gene engineering technologies, antibody fragments (Fab, ScFv) now have the advantages of low molecular weight and weak immunogenicity, but they have lower stability and affinity than full antibodies.
In 1993, scientists from Belgium first reported the existence of Heavy Chain antibodies (HCAbs) without the light chain in the blood of camelids. The variable domain (VHH) of the heavy chains of HCAbs has a complete and independent antigen-binding capacity, and if cloned, a single domain antibodies in the nanometer scale which are known as Nanobodies® (Nbs) can be obtained. A nanobody has many advantages as a ligand: 1) small molecular weight, strong tissue penetration, and high affinity. It has a molecular weight of only 15,000 which is the lowest molecular weight among the known antibody molecules; its ability to penetrate tissues is significantly superior to full antibody, and its affinity with specific antigen is of nmol scale. 2) Stable structure. It can maintain stability even if stored at 37° C. for a week, under high temperature (90° C.), or under strong denaturing conditions such as being exposed to chaotropic agent, protease and strong pH value. 3) Weak immunogenicity. As its gene has high homology with human VH III family, it has weak immunogenicity and good biocompatibility. Because of these advantages, nanobodies have been studied extensively as new antibody drugs, but their use as targeted ligands for SP-A has not been reported.